SIRPA enhances osteosarcoma metastasis by stabilizing SP1 and promoting SLC7A3-mediated arginine uptake

Peng Wang; Yihui Song; Hongyu Li; Jiahao Zhuang; Xin Shen; Wen Yang; Rujia Mi; Yixuan Lu; Biao Yang; Mengjun Ma; Huiyong Shen

doi:10.1016/j.canlet.2023.216412

SIRPA enhances osteosarcoma metastasis by stabilizing SP1 and promoting SLC7A3-mediated arginine uptake

Cancer Lett. 2023 Nov 1:576:216412. doi: 10.1016/j.canlet.2023.216412. Epub 2023 Sep 26.

Authors

Peng Wang¹, Yihui Song¹, Hongyu Li¹, Jiahao Zhuang¹, Xin Shen¹, Wen Yang¹, Rujia Mi², Yixuan Lu², Biao Yang¹, Mengjun Ma³, Huiyong Shen⁴

Affiliations

¹ Department of Orthopedics, The Eighth Affliated Hospital, Sun Yat-sen University, No. 3025 Shennan Zhong Road, Shenzhen, Guangdong, 518033, China.
² Center for Biotherapy, The Eighth Affliated Hospital, Sun Yat-sen University, No. 3025 Shennan Zhong Road, Shenzhen, Guangdong, 518033, China.
³ Department of Orthopedics, The Eighth Affliated Hospital, Sun Yat-sen University, No. 3025 Shennan Zhong Road, Shenzhen, Guangdong, 518033, China. Electronic address: mamj8@mail.sysu.edu.cn.
⁴ Department of Orthopedics, The Eighth Affliated Hospital, Sun Yat-sen University, No. 3025 Shennan Zhong Road, Shenzhen, Guangdong, 518033, China. Electronic address: shenhuiy@mail.sysu.edu.cn.

PMID: 37769797
DOI: 10.1016/j.canlet.2023.216412

Abstract

The function of signal regulatory protein alpha (SIRPA) has been well studied in macrophages and dendritic cells, but relatively less in tumors. Notably, SIRPA is upregulated in osteosarcoma tissues, particularly in metastatic tissues, and is associated with unfavorable clinical outcomes. Knockdown of SIRPA impaired OS cell migration by decreasing specificity protein 1 (SP1) stability and arginine uptake. Importantly, SIRPA phosphorylated SP1 at threonine 278 (Thr278) through extracellular signal-regulated kinase (ERK) activation to protect SP1 from proteasomal degradation. In addition, SP1 increased solute carrier family 7 member 3 (SLC7A3) expression by binding to the SLC7A3 promoter and increased the capability of arginine uptake, thereby facilitating OS cell migration. More interestingly, arginine promoted the stability of SP1 in an ERK-independent manner and thus formed the "SP1 stabilization circle". Combined treatment with the anti-SIRPA antibody and arginase, which blocked the circle, impaired tumor metastasis in mice bearing xenografts formed from SIRPA-overexpressing cells. In summary, our study demonstrates that the upregulation of SIRPA promotes OS metastasis via the "SP1 stabilization circle" and SLC7A3-mediated arginine uptake, which might serve as a target for OS treatment.

Keywords: Arginine; Metastasis; Osteosarcoma; SIRPA; SP1/SLC7A3.